Synthesis, antitubercular and anticancer activities of substituted furyl-quinazolin-3(4H)-ones

Article abstract of DOI:10.1002/ardp.200700096

Some novel substituted-3-{[(1E)-(substituted-2-furyl)-methylene]amino} quinazolin-4(3H)-one (5, 6, 7) a-f were synthesized by a multi-step process. These synthesized compounds are characterized by various spectroscopic techniques and evaluated for their antitubercular and anticancer activities. Biological activity indicated that some of the title compounds are potent antitubercular and anticancer agents.

Full text of DOI:10.1002/ardp.200700096

Arch. Pharm. Chem. Life Sci. 2007, 340, 635–641
N. M. Raghavendra et al.
635
Full Paper
Synthesis, Antitubercular and Anticancer Activities of
Substituted Furyl-quinazolin-3(4H)-ones
Nulgulmnalli M. Raghavendra1, Parameshwaran Thampi1, Purvarga M. Gurubasavarajaswamy1,
and Dharmarajan Sriram2
1 Medicinal Chemistry Research Laboratory, Acharya and B.M. Reddy College of Pharmacy, Bangalore,
Karnataka, India
2 Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science,
Pilani, Rajasthan, India
Some novel substituted-3-{[(1E)-(substituted-2-furyl)-methylene]amino}quinazolin-4(3H)-one (5, 6,
7) a–f were synthesized by a multi-step process. These synthesized compounds are characterized
by various spectroscopic techniques and evaluated for their antitubercular and anticancer activ-
ities. Biological activity indicated that some of the title compounds are potent antitubercular
and anticancer agents.
Keywords: anticancer activity / antitubercular activity / furans / quinazolin-4-ones /
Received: May 10, 2007; accepted: September 4, 2007
DOI 10.1002/ardp.200700096
exhibit a potential chemotherapeutic activity. This work
represents a continuation of our systematic studies of
quinazolin-3(4H)-ones as anticancer and antibacterial
agents [17]. In the present contribution, we report herein
the simple, novel and high yielding reactions of different
furan-2-aldehydes with various 3-amino-quinazolin-
4(3H)-ones to give substituted-3-{[(1E)-(substituted-2-
furyl)-methylene]amino}quinazolin-4(3H)-one (5, 6, 7) a–f.
The synthesized compounds were tested for their antitu-
bercular and anticancer activities.
Introduction
Substituted quinazolin-3(4H)-ones are among the versa-
tile heterocyclic compounds, as they have a broad spec-
trum of pharmacological activities like antitubercular
[1], anticancer [2–3], antibacterial [4], antifungal [5], anti-
HIV [6], anthelmintic [7], anti-inflammatory [8], and anti-
hypertensive activity [9]. It was also found that some of
substituted furans possess potential anticancer [10], anti-
tubercular [11], antibacterial [12], and antifungal activ-
ities [13]. Structure-activity relationship studies of the
quinazolinone ring system in the literature [14–16] sug-
gest that positions 2, 3, 6, and 8 are very much important
for chemotherapeutic activity. Thus, it seemed of interest
to combine the quinazolin-3(4H)-ones with substituted
furans in a single molecule as compounds of this type
can be expected to be biologically active and perhaps to
Results and discussion
Scheme 1 explains the reaction of different amino ben-
zoic acids with benzoylchloride / acid anhydrides to yield
substituted 4H-3,1-benzoxazin-4-ones (1, 2) a–c, which
upon condensation with hydrazine hydrate produced 3-
amino-substituted quinazolin-4(3H)-ones (3, 4) a–c. These
3-amino quinazolin-4(3H)-ones when treated with differ-
ent furan-2-aldehydes in the presence of acid catalyst
Correspondence: N. M. Raghavendra, Medicinal Chemistry Research
Laboratory, Acharya and B.M. Reddy College of Pharmacy, Bangalore-
560 090, India
form
substituted-3-{[(1E)-(substituted-2-furyl)methyle-
E-mail: nmraghu76@yahoo.co.in
Fax: +91 80 2839 3541
ne]amino}quinazolin-4(3H)-one (5, 6, 7) a–f. The infrared
spectra of the 3-amino-quinazolin-4(3H)-ones (3, 4) a–c
showed characteristic absorption bands at 3200–
3300 cm– 1 for amino (NH2), which disappeared by the for-
Abbreviations: Ehrlich Ascites Carcinoma (EAC); minimal inhibitory
concentration (MIC); percentage increase in life span (% ILS); mean sur-
vival time (MST)
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636
N. M. Raghavendra et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 635–641
mation of substituted-3-{[(1E)-(substituted-2-furyl)methy-
lene]amino}quinazolin-4(3H)-one (5, 6, 7) a–f. Similarly,
the 1H-NMR spectra of title compounds (5, 6, 7) a–f
showed characteristic singlets at d 8.6-9.2 due to the
N=CH proton. Signals at d 6.3–7.5 due to furyl protons
established that all the 3-amino-quinazolin-4(3H)-ones (3,
4) a–c are converted into substituted-3-{[(1E)-(substituted-
2-furyl)methylene]amino}quinazolin-4(3H)-one (5, 6, 7)
a–f. Quinazolin-4-one and furan orient themselves on
opposite sides of the C=N bond due to steric hindrance.
Hence, all the title compounds have stable E-configura-
tion at the C=N bond at position 3 of quinazolin-4-one as
determined by ACD/Chemsketch software. The syntheses
of compounds (5, 6, 7) a–f are mentioned in Scheme 1
and their reaction parameters are given in Table 2. The
physical data for the intermediates (1–4) a–c are given in
Table 1.
Scheme 1. Synthesis of presented compounds.
Table 1. Physical constants of the intermediates 1–4 a–c.
Intermedi- Mp
Rf
Inter-
Mp
Rf
ates
(8C)
mediates (8C)
In-vitro antitubercular activity indicates that some of
the tested compounds are promising candidates having a
good activity against M. tuberculosis H37Rv and M. smegma-
tis. Compounds 6c, 7d, 7f, and 7c showed more activity
than standard ciprofloxacin. Compound 6a was found to
be equipotent to ciprofloxacin against M. tuberculosis.
1a
1b
1c
2a
2b
2c
109
182
092
122
169
115
0.92
0.7
0.94
0.34
0.67
0.87
3a
3b
3c
4a
4b
4c
172
155
235
172
225
182
0.38
0.41
0.63
0.11
0.33
0.57
Table 2. Physical parameters and in-vitro antitubercular activity of compounds 5–7 a–f.
Compounds
X
X1
R
R1
Yield
(%)
Mp
(8C)
Rf
MIC (lg/mL)
M. tuberculosis
MIC (lg/mL)
M. smegmatis
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
H
H
H
Br
H
H
Br
H
Br
Br
H
Br
Br
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
C3H7
CH3
H
H
H
CH3
CH3
CH3
H
H
H
CH3
CH3
CH3
NO2
NO2
NO2
NO2
NO2
NO2
50
55
65
70
45
65
50
60
70
50
70
75
50
65
75
60
70
78
165
190
157
120
191
205
206
220
195
185
230
192
242
260
240
197
243
205
0.62
0.45
0.48
0.32
0.37
0.48
0.31
0.48
0.71
0.60
0.48
0.80
0.02
0.93
0.48
0.30
0.37
0.42
> 12.5
12.5
50
50
100
50
50
50
12.5
12.5
0.78
50
50
50
Br
Br
H
> 12.5
> 12.5
> 12.5
> 12.5
1.56
3.13
0.2
> 12.5
> 12.5
> 12.5
6.25
Br
Br
Br
Br
Br
Br
Br
Br
H
Br
Br
Br
Br
Br
CH3
C3H7
C6H5
C6H5
C6H5
CH3
25
25
H
Br
H
Br
Br
6.25
0.78
0.78
3.13
0.78
1.56
0.05
6.25
3.13
12.5
3.13
a 0.78
6.25
7e
7f
CH3
C3H7
Ciprofloxacin
Isoniazid
–
–
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Arch. Pharm. Chem. Life Sci. 2007, 340, 635–641
Novel Substituted Furyl-quinazolin-3(4H)-ones
In-vivo anticancer activity
637
Table 3. In-vitro and in-vivo anticancer activity of compounds 5–7 a–f.
Compounds In-vitro anticancer activity Percentage cytotoxicity
of drug at various concentrations on EAC cells
(lg/mL)
1000
500
250
125
Gain in body
weight
Percentage
decrease in
body weight
MSTa) l S.E.b)
% ILS
Control
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
7a
7b
7c
–
–
–
–
5.46 l 0.19
1.24 l 0.087
3.78 l 0.398
0.84 l 0.0244
ND
ND
ND
0.74 l 0.06
ND
ND
–
14.6 l 0.21
25.0 l 0.44
18.6 l 1.33
33.5 l 0.76
ND
ND
ND
36.6 l 1.2
ND
ND
ND
ND
ND
ND
24.1 l 0.30
21.0 l 0.36
26.0 l 0.57
ND
16.0 l 0.36
32.0 l 0.68
–
46.8
66.7
80.6
25.4
20.2
18.5
81.9
20.0
30.9
20.5
19.5
17.0
33.3
41.0
75.0
50.0
13.7
43.8
86.7
39.6
32.7
47.6
24.5
20.2
18.5
38
18.6
25.0
18.2
18.5
15.4
26.2
34.4
50.8
38.4
13.4
42.3
69.0
33.4
30.0
41.6
24.5
18.2
17.5
28.5
13.4
20.0
15.0
18.5
15.4
16.3
25.0
36.6
25.0
13.4
16.7
46.0
16.7
16.7
30.0
18.0
18.2
18.5
13.4
13.4
8.3
15.4
10.0
15.4
16.3
15.0
16.7
13.4
13.4
13.4
43.0
77.28
30.76
84.61
ND
ND
ND
86.44
ND
ND
ND
ND
71.23***
27.39*
129.45***
ND
ND
ND
150.68***
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
0.84 l 0.024
1.62 l 0.1463
0.92 l 0.037
ND
4.02 l 0.037
0.9 l 0.1183
84.61
70.32
83.15
ND
26.37
83.51
65.06***
43.83***
78.08***
ND
9.58*
119.17***
7d
7e
7f
Vincristine
a)
Mean survival time.
Standard error.
Not determined.
b)
c)
* P a 0.05; *** P a 0.0001.
Compounds 6b, 7e, 7a, and 7b were moderately active 7c, f (MIC 0.78 lg/mL) favors antitubercular activity
(Table 2). against M. tuberculosis compared to non-halogen deriv-
In-vivo and in-vitro anticancer activity studies against atives as in compound 5a (MIC A 12.5 lg/mL) and 7a (MIC
Ehrlich Ascites Carcinoma (EAC) indicated that com- 6.25 lg/mL). Alkyl substitutions are more effective than
pounds 6a and 5c exhibited the highest degree of anti- aryl substitution at position 2 of quinazolinone, as com-
cancer activity compared to standard vincristine pound 6a (MIC 1.56 lg/mL) is more potent than com-
(Table 3). Compound 7c exhibited good in-vitro and mod- pound 5b (MIC 12.5 lg/mL).
erate in-vivo anticancer activity. Compounds 5b, 7d, 5a,
Structure-activity analysis of the synthesized com-
7f, and 7b had moderate anticancer activity. Other com- pounds for anticancer activity indicates that the pres-
pounds had no significant anticancer activity.
ence of a bromine at position 6 and 8 of quinazolinone as
in compound 5c (% ILS, 129.45) increases the percentage
increase in life span (% ILS) as compared to non-halogen
derivative compound 5a (% ILS, 71.23). Interestingly,
attachment of unsubstituted furan as in compound 6a (%
Conclusions
Structure-activity relationship studies of the title com- ILS, 150.68) is found to be more beneficial than nitro
pounds for antitubercular activity indicates unsubsti- furan and methyl furan as in compounds 7d (% ILS,
tuted furan or furan with electron-withdrawing group as 78.08) and 6d (% ILS, not determined as its in-vitro activity
in compounds 6c ((minimal inhibitory concentrations) was negligible), respectively. Methyl or phenyl substitu-
MIC 0.2 lg/mL), 7d (MIC 0.78 lg/mL) seems to be more tion at position 2 of quinazolinone as in compounds 5a,
effective than furans having electron-donating group at 5c, 6a, 7b, 7c, and 7d prove more effective than the propyl
position 3 of the quinazolinone ring as in compound 6f analogues 7f (% ILS, 9.58) and 6f (% ILS, not determined as
(MIC A 12.5 lg/mL). An electron-withdrawing group on its in vitro activity was negligible).
the aromatic portion of quinazolinone as in compounds
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638
N. M. Raghavendra et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 635–641
water and dried. Compounds 2a–c thus obtained were used in
the next step without further purification. IR spectra of these
compounds show intense peaks at 3030 (aromatic C-H stretch-
ing), 2987, 2817 cm– 1 (CH3 C-H stretching), 1749 cm– 1 (C=O
stretching), 1506, 1444 cm– 1 (C=C ring stretching), 694 cm– 1 (C-
Br stretching). 1H-NMR spectra of these compounds showed aro-
matic peaks at d 7.5–8.5 and alkyl peaks at d 1.0–2.48 (s, 3H,
CH3).
In summary, with respect to these observations, we
conclude that this series could be developed as a novel
class of antitubercular and anticancer agents. However,
further structural evaluation and pharmacological
screening on different types of cancer cell lines is
required to select the best possible potent molecule
among the series.
General procedure for synthesis of 3-amino-2-aryl/
alkylquinazolin-4(3H)-one (3, 4) a-c
The authors are thankful to the Indian Institute of Science, Ban-
galore, for the spectral analysis. The authors are also thankful
to Sri. Premnath Reddy, Chairman; Acharya Institutes and Dr.
Divakar Goli, Principal; Acharya and B. M. Reddy College of
Pharmacy, Bangalore, for the laboratory facilities.
Various benzoxazin-4-ones (1, 2) a–c (0.01 mol) were refluxed
with hydrazine hydrate (50 mL) for 3 h with occasional shaking.
The reaction mixtures were cooled to room temperature. The
crystals formed were filtered, washed with water, dried, and
used in the next step without purification. IR spectra of these
compounds show intense peaks at 3300, 3200 cm– 1 for amino
(NH2), 3060 cm– 1 for aromatic (C-H), 1660 cm– 1 for carbonyl
(C=O) and 1560, 1470 cm– 1 for the aromatic ring (C=C) stretch-
The authors have declared no conflict of interest.
1
ing. H-NMR spectra of these compounds showed aromatic sig-
Experimental
nals at d 7.0–8.5, amino NH2 signals at d 5.0–5.5 as singlet and
alkyl signals at d 1–3.
Chemistry
Melting points are uncorrected. IR spectra (cm– 1) were recorded
on Shimadzu-8400 FTIR spectrophotometer (Shimadzu, Tokyo,
Japan), NMR spectra on Brucker 400 MHz spectrometer (Bruker
Bioscience, Billerica, MA, USA) and mass spectra on Micromass
Q-tof Mass spectrometer (Micromass, Manchester, UK), Shi-
madzu QP 5050A and Shimadzu LCMS 2010A Mass spectrome-
ter. Micro analysis was done using Thermo Finnigan FLASH EA
1122 CHNS analyzer (Thermo Electron Corporation, Bremen,
Germany). The purity of the compounds were checked on silica
gel 60 F254 coated aluminum TLC plates (Merck, Darmstadt, Ger-
many) by using ethyl acetate and petroleum ether (1 : 4) as
mobile phase and observed in UV light. Spectral data (IR, NMR,
and mass spectra) confirmed the structures of synthesized com-
pounds and the purity of these compounds was ascertained by
microanalysis. Elemental (C, H, N) analyses indicated that the
calculated and observed values were within the acceptance lim-
its (l 0.4%). All chemicals and reagents were obtained from Lan-
caster (UK) and Merck (India) and were used without further
purification.
General procedure for synthesis of substituted-3-{[(1E)-
(substituted-2-furyl)/(2-furyl)-methylene]amino}-
quinazolin-4(3H)-one (5, 6) a–f
Different 3-amino-substituted-quinazolin-4(3H)-ones (3, 4) a–c
(0.006 mol) were dissolved in 50 mL of warm alcohol (dioxan for
3c). To these, two drops of concentrated hydrochloric acid, fol-
lowed by different furan-2-aldehydes (0.0062 mol) were added
and refluxed for 5–6 h. On cooling, the crystals obtained were
filtered, washed with petroleum ether, dried, and recrystallized
from ethyl acetate to give (5, 6) a–f.
3-{[(1E)-2-Furylmethylene]amino}-2-phenylquinazolin-
4(3H)-one 5a
IR (KBr), m (cm– 1): 3033 (aromatic C-H stretching), 1677 (C=O,
stretching), 1602 (C=N stretching), 1558, 1473 (C=C ring stretch-
ing), 1355 (C-N stretching); 1H-NMR, d: 8.8–8.9 (s, 1H, N=CH),
8.2–8.26 (d, 1H, Ar-H), 7.7–7.8 (t, 1H, Ar-H), 7.4–8.1 (m, 7H, Ar-
H), 7.2–7.3 (d, 1H, furan), 7.08–7.1 (d, 1H, furan), 6.7–6.78 (dd,
1H, furan); MS (m/z): 315 [M]+. Anal. Calcd. (%) for C19H13N3O2: C,
72.37; H, 4.16; N, 13.33. Found: C, 72.65; H, 4.42; N, 13.26.
General procedure for synthesis of substituted-2-aryl-4H-
3,1-benzoxazin-4-one 1a-c
Different 2-amino benzoic acids (0.1 mol) were dissolved in
50 mL of pyridine. To this reaction mixture, benzoyl chloride
(11.7 mL) was added with stirring at 278C and stirring was con-
tinued for 20 min. Precipitates obtained were filtered, washed
with petroleum ether, water, dried, and recrystallized from
ethyl acetate as shining yellow crystals. IR spectra of these com-
pounds show intense peaks at 3060 cm– 1 (aromatic C-H stretch-
ing), 1766 cm– 1 (C=O stretching), 1575, 1450 cm– 1 (C=C ring
stretching), 692 cm– 1 (C-Br stretching). 1H-NMR spectra of these
compounds showed aromatic peaks at d 7.5–8.5.
6-Bromo-3-{[(1E)-2-furylmethylene]amino}-2-
phenylquinazolin-4(3H)-one 5b
IR (KBr), m (cm– 1): 3030 (aromatic C-H stretching), 1672 (C=O,
stretching), 1610 (C=N stretching), 1569, 1469 (C=C ring stretch-
ing), 1313 (C-N stretching), 686 (C-Br stretching); 1H-NMR, d: 8.8–
8.9 (s, 1H, N=CH), 8.28–8.3 (s, 1H, Ar-H), 7.4–8.08 (m, 7H, Ar-H),
7.2–7.3 (d, 2H, furan), 6.7–6.78 (s, 1H, furan); MS (m/z): 394 [M]+.
Anal. Calcd. (%) for C19H12BrN3O2: C, 57.89; H, 3.07; N, 10.66.
Found: C, 57.78; H, 3.42; N, 10.61
General procedure for the synthesis of substituted-2-
6,8-Dibromo-3-{[(1E)-2-furylmethylene]amino}-2-
alkyl-4H-3,1-benzoxazin-4-one 2a–c
phenylquinazolin-4(3H)-one 5c
Different 2-amino benzoic acids (0.01 mol) were refluxed with
different acid anhydrides (40 mL) for 90 min. The reaction mix-
tures were cooled, crystals obtained were filtered, washed with
IR (KBr), m (cm– 1): 3082 (aromatic C-H stretching), 1741 (C=O
stretching), 1679 (C=N stretching), 1566, 1473 (C=C ring stretch-
1
ing), 1350 (C-N stretching), 690 (C-Br stretching); H-NMR, d: 8.8
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Arch. Pharm. Chem. Life Sci. 2007, 340, 635–641
Novel Substituted Furyl-quinazolin-3(4H)-ones
639
(s, 1H, N=CH), 8.45 (s, 1H, Ar-H), 8.28 (s, 1H, Ar-H), 7.4-8 (m, 5H, Ar-
H), 7.2–7.3 (d, 2H, furan), 6.7–6.78 (s, 1H, furan); MS (m/z): 473.6
[M]+. Anal. Calcd. (%) for C19H11Br2N3O2: C, 48.23; H, 2.34; N, 8.88.
Found: C, 48.45; H, 2.57; N, 8.72.
6,8-Dibromo-3-{[(1E)-2-furylmethylene]amino}-2-
propylquinazolin-4(3H)-one 6c
IR (KBr), m (cm– 1): 3086 (aromatic C-H stretching), 2981, 2939
(CH3, C-H stretching), 1672 (C=O stretching), 1616 (C=N stretch-
ing), 1596, 1477 (C=C ring stretching), 1317 (C-N stretching), 792
(CH2, C-H bending), 694 (C-Br stretching); 1H-NMR, d: 8.75 (s, 1H,
N=CH), 8.35 (s, 1H, Ar-H), 8.2 (s, 1H, Ar-H), 8.1 (s, 1H, furan), 7.4 (d,
1H, furan), 6.8 (m, 1H, furan), 2.8–2.9 (dd, 4H, CH2), 1.2–1.3 (t,
3H, CH3); MS (m/z): 439.5 [M]+. Anal. Calcd. (%) for C16H13Br2N3O2:
C, 43.76; H, 2.98; N, 9.57. Found: C, 43.51; H, 2.75; N, 9.87.
3-{[(1E)-(5-Methyl-2-furyl)methylene]amino}-2-
phenylquinazolin-4(3H)-one 5d
IR (KBr), m (cm– 1): 3035 (aromatic C-H stretching), 2927, 2854
(CH3, C-H stretching), 1753 (C=O stretching), 1681 (C=N stretch-
ing), 1562, 1473 (C=C ring stretching), 1325 (C-N stretching), 692
(C-Br stretching); 1H-NMR, d: 8.7 (s, 1H, N=CH), 8.2–8.3 (d, 1H, Ar-
H), 7.8–7.9 (t, 1H, Ar-H), 7.4–7.8 (m, 7H, Ar-H), 7.1–7.2 (d, 1H,
furan), 6.4 (d, 1H, furan), 2.35 (s, 3H, CH3); MS (m/z): 329.9 [M]+.
Anal. Calcd. (%) for C20H15N3O2: C, 72.94; H, 4.59; N, 12.76. Found:
C, 72.87; H, 4.82; N, 12.54.
6-Bromo-2-methyl-3-{[(1E)-(5-methyl-2-
furyl)methylene]amino}quinazolin-4(3H)-one 6d
IR (KBr), m (cm– 1): 3062 (aromatic C-H stretching), 2923, 2852
(CH3, C-H stretching), 1672 (C=O stretching), 1620 (C=N stretch-
ing), 1571, 1467 (C=C ring stretching), 1313 (C-N stretching), 692
(C-Br stretching); 1H-NMR, d: 8.6 (s, 1H, N=CH), 8.2 (s, 1H, Ar-H),
7.9–8 (d, 2H, Ar-H), 7.6 (d, 1H, furan), 6.48 (s, 1H, furan), 2.43 (s,
3H, CH3), 2.1 (s, 3H, CH3); MS (m/z): 346 [M]+. Anal. Calcd. (%) for
C15H12BrN3O2: C, 52.04; H, 3.49; N, 12.14. Found: C, 52.05; H, 3.54;
N, 12.50.
6-Bromo-3-{[(1E)-(5-methyl-2-furyl)methylene]amino}-2-
phenylquinazolin-4(3H)-one 5e
IR (KBr), m (cm– 1): 3058 (aromatic C-H stretching), 2917, 2824
(CH3, C-H stretching), 1679 (C=O stretching), 1641 (C=N stretch-
ing), 1556, 1444 (C=C ring stretching), 1305 (C-N stretching), 692
(C-Br stretching); 1H-NMR, d: 8.7 (s, 1H, N=CH), 8.5–8.6 (d, 1H, Ar-
H), 8.2 (s, 1H, Ar-H), 7.4–8.15 (m, 6H, Ar-H), 6.8–7.2 (d, 1H, furan),
6.3–6.4 (d, 1H, furan), 2.34 (s, 3H, CH3); MS (m/z): 409 [M]+. Anal.
Calcd. (%) for C20H14BrN3O2: C, 58.84; H, 3.46; N, 10.29. Found: C,
58.95; H, 3.54; N, 10.58.
6,8-Dibromo-2-methyl-3-{[(1E)-(5-methyl-2-
furyl)methylene]amino}quinazolin-4(3H)-one 6e
IR (KBr), m (cm– 1): 3076 (aromatic C-H), 2958, 2923 (CH3 C-H), 1674
1
(C=O), 1610 (C=N), 1593, 1446 (C=C), 1309 (C-N), 694 (C-Br); H-
NMR, d: 8.56 (s, 1H, N=CH), 8.37 (s, 1H, Ar-H), 8.21 (s, 1H, Ar-H),
7.28 (d, 1H, furan), 6.48 (d, 1H, furan), 2.45 (s, 3H, CH3), 2.42 (s,
3H, CH3); MS (m/z): 425 [M]+. Anal. Calcd. (%) for C15H11Br2N3O2: C,
42.38; H, 2.61; N, 9.89. Found: C, 42.47; H, 2.72; N, 10.13.
6,8-Dibromo-3-{[(1E)-(5-methyl-2-
furyl)methylene]amino}-2-phenylquinazolin-4(3H)-one 5f
IR (KBr), m (cm– 1): 3074 (aromatic C-H stretching), 2927, 2844
(CH3, C-H stretching), 1679 (C=O stretching), 1608 (C=N stretch-
ing), 1575, 1448 (C=C ring stretching), 1315 (C-N stretching), 694
(C-Br stretching); 1H-NMR, d: 8.68 (s, 1H, N=CH), 8.45 (s, 1H, Ar-H),
8.28 (s, 1H, Ar-H), 7.4–7.7 (m, 5H, Ar-H), 7.2 (d, 1H, furan), 6.4 (d,
1H, furan), 2.35 (s, 3H, CH3); MS (m/z): 487.5 [M]+. Anal. Calcd. (%)
for C20H13Br2N3O2: C, 49.31; H, 2.69; N, 8.63. Found: C, 49.70; H,
2.75; N, 8.91.
6,8-Dibromo-3-{[(1E)-(5-methyl-2-
furyl)methylene]amino}-2-propylquinazolin-4(3H)-one 6f
IR (KBr), m (cm– 1): 3083 (aromatic C-H stretching), 2981, 2933
(CH3, C-H stretching), 1672 (C=O stretching), 1620 (C=N stretch-
ing), 1519, 1444 (C=C ring stretching), 1365 (C-N stretching), 792
(CH2, C-H bending), 719 (C-Br stretching);1H-NMR, d: 8.6 (s, 1H, Ar-
H), 8.4 (s, 1H, N=CH), 8.2 (s, 1H, Ar-H), 7.1 (d, 1H, furan), 6.48 (d,
1H, furan), 2.8–2.9 (m, 4H, CH2), 2.43 (s, 3H, CH3), 1.2–1.3 (t, 3H,
CH3); MS (m/z): 453 [M]+. Anal. Calcd. (%) for C17H15Br2N3O2: C,
45.06; H, 3.34; N, 9.27. Found: C, 45.34; H, 3.59; N, 9.50.
6-Bromo-3-{[(1E)-2-furylmethylene]amino}-2-
methylquinazolin-4(3H)-one 6a
IR (KBr), m (cm– 1): 3083 (aromatic C-H stretching), 2927, 2835
(CH3, C-H stretching), 1672 (C=O stretching), 1620 (C=N stretch-
ing), 1596, 1469 (C=C ring stretching), 1317 (C-N stretching), 694
(C-Br stretching); 1H-NMR, d: 8.76 (s, 1H, N=CH), 8.2 (d, 1H, Ar-H),
8.1 (s, 1H, Ar-H), 7.9–8.1 (d, 1H, Ar-H), 7.58–7.62 (d, 1H, furan),
7.35 (d, 1H, furan), 6.8 (s, 1H, furan); MS (m/z): 332 [M]+. Anal.
Calcd. (%) for C14H10BrN3O2: C, 50.62; H, 3.03; N, 12.65. Found: C,
50.99; H, 2.72; N, 12.82.
General procedure for synthesis of substituted-3-{[(1E)-
(5-nitro-2-furyl)methylene]amino}quinazolin-4(3H)-one
7a–f
(5-Nitro-2-furyl)methylene diacetate (0.0063 mol) was warmed in
a mixture of 10 mL alcohol, 2 mL water, and 0.2 mL concen-
trated hydrochloric acid for 20 min. To this, different 3-amino-
substituted-quinazolin-4(3H)-ones (3, 4) a–c (0.006 mol) in 50 mL
of warm alcohol (dioxan for 5c) were added and refluxed for 5–
6 h. On cooling, the crystals obtained were filtered, washed with
petroleum ether, dried, and recrystallized from ethyl acetate to
give 7a–f.
6,8-Dibromo-3-{[(1E)-2-furylmethylene]amino}-2-methyl
quinazolin-4(3H)-one 6b
IR (KBr), m (cm– 1): 3083 (aromatic C-H), 2927, 2835 (CH3, C-H),
1670 (C=O), 1616 (C=N), 1596, 1469 (C=C), 1317 (C-N), 692 (C-Br);
1H-NMR, d: 8.75 (s, 1H, N=CH), 8.35 (s, 1H, Ar-H), 8.2 (s, 1H, Ar-H),
7.9–8.1 (d, 1H, furan), 7.3–7.4 (d, 1H, furan), 6.8 (m, 1H, furan),
2.55 (s, 3H, CH3); MS (m/z): 411.9 [M + H]+. Anal. Calcd. (%) for
C14H9Br2N3O2: C, 40.91; H, 2.21; N, 10.22. Found: C, 41.29; H, 2.54;
N, 10.26.
3-{[(1E)-(5-Nitro-2-furyl)methylene]amino}-2-
phenylquinazolin-4(3H)-one 7a
IR (KBr), m (cm– 1): 3030 (aromatic C-H stretching), 1692 (C=O
stretching), 1620 (C=N stretching), 1550, 1451 (C=C ring stretch-
ing), 1336 (C-NO2 stretching); 1H-NMR, d: 9.2 (s, 1H, N=CH), 8.2–
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Arch. Pharm. Chem. Life Sci. 2007, 340, 635–641
8.3 (d, 2H, Ar-H), 7.5–8 (m, 9H, Ar-H + furan); MS m/z: 361 [M +
H]+. Anal. Calcd. (%) for C19H12N4O4: C; 63.33, H; 3.36, N; 15.55.
Found: C; 63.53, H; 3.57, N; 15.82.
Biological evaluation
Antitubercular activity
Compounds (5, 6, 7) a–f were evaluated for their in-vitro antitu-
bercular activity by agar dilution method [18] against M. tubercu-
losis H37Rv and M. smegmatis. The agar dilution method was per-
formed using Middle brook 7H10 medium supplemented with
Middle brook OADC medium (Hi-Media Lab., Mumbai, India).
After solidification of the agar, the plates were inoculated with
0.1 mL of 10– 4 dilutions of a McFarland 1.0 concentration of a
suspension of organism. The inoculated plates were then incu-
bated at 378C for 4 weeks. The concentrations of the test com-
pounds used were 0.19, 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, and
50 lg/mL. The minimum inhibitory concentration (MIC) was
considered to be the lowest concentration that completely
inhibited growth on agar plates, disregarding a single colony or
a faint haze caused by the inoculums.
6-Bromo-3-{[(1E)-(5-nitro-2-furyl)methylene]amino}-2-
phenylquinazolin-4(3H)-one 7b
IR (KBr), m (cm– 1): 3030 (aromatic C-H stretching), 1681 (C=O
stretching), 1602 (C=N stretching), 1531, 1440 (C=C ring stretch-
1
ing), 1342 (C-NO2 stretching), 692 (C-Br stretching); H-NMR, d:
9.15 (s, 1H, N=CH), 8.3 (s, 1H, Ar-H), 8–8.1 (dd, 2H, Ar-H), 7.4–7.8
(m, 7H, Ar-H + furan); MS m/z: 440.9 [M + H]+. Anal. Calcd. (%) for
C19H11BrN4O4: C; 51.96, H; 2.52, N; 12.76. Found: C; 52.0, H; 2.93,
N; 12.44.
6,8-Dibromo-3-{[(1E)-(5-nitro-2-furyl)methylene]amino}-
2-phenylquinazolin-4(3H)-one 7c
Anticancer activity
IR (KBr), m (cm– 1): 3030 (aromatic C-H), 1681 (C=O), 1602 (C=N),
1562, 1446 (C=C), 1340 (C-NO2), 692 (C-Br); 1H-NMR, d: 9.13 (s, 1H,
N=CH), 8.23 (s, 1H, Ar-H), 7.98–8.03 (d, 1H, Ar-H), 7.8–7.9 (d, 1H,
Ar-H), 7.6–7.7 (dd, 2H, furan), 2.65 (s, 3H, CH3); MS (m/z): 518.9
[M + H]+. Anal. Calcd. (%) for C19H10Br2N4O4: C, 44.04; H, 1.95; N,
10.81. Found: C, 44.0; H, 2.30; N, 10.47.
In-vitro anticancer activity of compounds (5, 6, 7) a–f against EAC
cells was determined by trypan blue exclusion method [19]. The
EAC cells were collected, counted, and adjusted to 106 cells/mL
with normal saline. The drug dilutions were made with phos-
phate buffer saline (PBS) and were further adjusted to concentra-
tions ranging from 125-1000 lg/mL. The drug dilutions were
then added to the EAC cells and incubated at 378C for 3 h. At the
end of 3 h, the cell viability was determined and percentage
cytotoxicity was calculated. The percentage cytotoxicity was cal-
culated using the formula
6-Bromo-2-methyl-3-{[(1E)-(5-nitro-2-
furyl)methylene]amino}quinazolin-4(3H)-one 7d
IR (KBr), m (cm– 1): 3083 (aromatic C-H stretching), 2937, 2845
(CH3, C-H stretching), 1674 (C=O stretching), 1614 (C=N stretch-
ing), 1533, 1496 (C=C ring stretching), 1330 (C-NO2 stretching),
692 (C-Br stretching); 1H-NMR, d: 9.13 (s, 1H, N=CH), 8.23 (s, 1H,
Ar-H), 7.98–8.03 (d, 1H, Ar-H), 7.8–7.9 (d, 1H, Ar-H), 7.6–7.7 (dd,
2H, furan), 2.65 (s, 3H, CH3); MS (m/z): 377 [M]+. Anal. Calcd. (%)
for C14H9BrN4O4: C, 44.58; H, 2.41; N, 14.86. Found: C, 44.67; H,
2.57; N, 14.78.
Percentage cytotoxicity = 100 – Tc –Dc/Tc6100
where Tc = total EAC cells and Dc = dead EAC cells [17].
Compounds 5a-c, 6a and 7 (b–d, f) with significant in-vitro
anticancer activity were further selected for screening in-vivo
anticancer activity by determining different parameters like
body weight analysis, mean survival time (MST) and percentage
increase in life span (% ILS) [20]. The EAC cells containing 106
cells/0.1 mL of phosphate buffer saline were injected into the
peritoneal cavity of all the animals (six swiss albino mice in each
group). Treatment with test compounds (80 mg/kg body weight)
and the standard vincristine (520 lg/kg body weight) was started
24 h after inoculation of cancer cells, once daily as a single dose
in 0.3% CMC suspension by intraperitoneal route for 10 days. All
the mice were weighed daily up to 11 days. The decrease in body
weight and MST of the test and standard group animals were
compared with control group. Results are shown in Table 3. Per-
centage decrease in the body weight was determined by using
the formula, percentage decrease in body weight = (Gc –Gt) /
Gc6100, where Gc = gain in body weight of control group, and Gt
= gain in body weight of treated group. Percentage increase in
life span was calculated by the formula,% ILS = (MST of treated
group – MST of control group) / MST of control group 6 100. Stu-
dent t-test was performed to ascertain the significance of the
exhibited activity.
6,8-Dibromo-2-methyl-3-{[(1E)-(5-nitro-2-
furyl)methylene]amino}quinazolin-4(3H)-one 7e
IR (KBr), m (cm– 1): 3080 (aromatic C-H stretching), 2922, 2852
(CH3 C-H stretching), 1681 (C=O stretching), 1616 (C=N stretch-
ing), 1569, 1487 (C=C ring stretching), 1348 (C-NO2 stretching),
692 (C-Br stretching); 1H-NMR, d: 9.09 (s, 1H, N=CH), 8.4 (s, 1H, Ar-
H), 8.23 (s, 1H, Ar-H), 7.8–7.9 (d, 1H, furan), 7.6–7.7 (d, 1H,
furan), 2.55 (s, 3H, CH3); MS (m/z): 456 [M]+, 479 [M + Na]+. Anal.
Calcd. (%) for C14H8Br2N4O4: C, 36.87; H, 1.77; N, 12.29. Found: C,
36.67; H, 1.97; N, 12.52.
6,8-Dibromo-3-{[(1E)-(5-nitro-2-furyl)methylene]amino}-
2-propylquinazolin-4(3H)-one 7f
IR (KBr), m (cm– 1): 3072 (aromatic C-H stretching), 2970, 2928
(CH3 C-H stretching), 1662 (C=O stretching), 1610 (C=N stretch-
ing), 1529, 1446 (C=C ring stretching), 1353 (C-N stretching), 759
(CH2, C-H bending), 692 (C-Br stretching); 1H-NMR, d: 9.08 (s, 1H,
N=CH), 8.4 (s, 1H, Ar-H), 8.23 (s, 1H, Ar-H), 7.85–7.9 (d, 1H, furan),
7.65–7.7 (d, 1H, furan), 2.8–2.9 (dd, 4H, CH2), 1.2–1.3 (t, 3H,
CH3); MS (m/z): 484 [M]+. Anal. Calcd. (%) for C16H12Br2N4O4: C,
39.70; H, 2.50; N, 11.57. Found: C, 39.53; H, 2.34; N, 11.95.
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